Cigarette smoking is one of the most significant public health concerns facing this nation as well as countries abroad. The prevalence and impact of tobacco use are greater than any other drugs of abuse. Many current smokers want to quit smoking, however few are successful when they quit on their own. Furthermore, even with intensive behavioral effectiveness of these treatments among a broad-based population of smokers is likely to be even less. In order to address this public health concern, innovative, easily administered treatment must be developed. In the past three years, investigators in our laboratory and at Texas have been testing the effects of a nicotine vaccine in animal studies. The results from these studies look very promising. These studies have characterized a highly immunogenic vaccine that elicits nicotine-specific antibodies of high affinity and specificity, a significant reduction in the distribution of nicotine to the brain even with repeated doses of nicotine, and a reduction in locomoter activity, blood pressure, and ACTH release in response to nicotine. In addition, immunization was observed to block the effects of nicotine in relieving withdrawal symptoms. Two human studies of this vaccine are proposed that will be conducted in the third and fourth year of the grant period after further animal toxicity and efficacy studies. The goal of the of the first study will be to determine the immunogenicity, safety and preliminary efficacy of the nicotine of the nicotine vaccine among smokers among smokers and ex-smokers randomly assigned in a double-blind manner to one of the three doses of nicotine vaccine or placebo. The primary outcome measures are the concentration and affinity of antibody titers, time and number of doses to achieve maximum nicotine specific antibody titers and safety. The results of this study will help determine the dose and number of booster doses to be used in the subsequent study. This second study will be a clinical trial to determine the efficacy of the nicotine vaccine as a smoking cessation aid. Smokers (N=300) will be randomly assigned to active nicotine vaccine or placebo vaccine and will be seen on a regular basis for the first 8 weeks and at 12 and 26 weeks after the primary vaccination. The primary outcome measures will be 4 weeks of continuous abstinence at the end of treatment and prevalence of sustained abstinence. The results from this study will address whether this nicotine vaccine will be a feasible and effective treatment for nicotine dependence.